Arylation with unsymmetrical diaryliodonium salts: A chemoselectivity study

Article abstract of DOI:10.1002/chem.201300860

Phenols, anilines, and malonates have been arylated under metal-free conditions with twelve aryl(phenyl)iodonium salts in a systematic chemoselectivity study. A new "anti-ortho effect" has been identified in the arylation of malonates. Several "dummy groups" have been found that give complete chemoselectivity in the transfer of the phenyl moiety, irrespective of the nucleophile. An aryl exchange in the diaryliodonium salts has been observed under certain arylation conditions. DFT calculations have been performed to investigate the reaction mechanism and to elucidate the origins of the observed selectivities. These results are expected to facilitate the design of chiral diaryliodonium salts and the development of catalytic arylation reactions that are based on these sustainable and metal-free reagents. Copyright

Full text of DOI:10.1002/chem.201300860

DOI: 10.1002/chem.201300860
Arylation with Unsymmetrical Diaryliodonium Salts:
A Chemoselectivity Study
Joel Malmgren, Stefano Santoro, Nazli Jalalian, Fahmi Himo,* and Berit Olofsson*[a]
Abstract: Phenols, anilines, and malo-
nates have been arylated under metal-
free conditions with twelve aryl-
ACHTUNGTRENNUNG(phenyl)iodonium salts in a systematic
chemoselectivity study. A new “anti-
ortho effect” has been identified in the
transfer of the phenyl moiety, irrespec-
tive of the nucleophile. An aryl ex-
change in the diaryliodonium salts has
been observed under certain arylation
conditions. DFT calculations have been
performed to investigate the reaction
mechanism and to elucidate the origins
of the observed selectivities. These re-
sults are expected to facilitate the
design of chiral diaryliodonium salts
and the development of catalytic aryla-
tion reactions that are based on these
sustainable and metal-free reagents.
Keywords: arylation · chemoselec-
tivity · DFT calculations · hyperva-
lent compounds · ligand exchange
arylation
of
malonates.
Several
“dummy groups” have been found that
give complete chemoselectivity in the
Introduction
However, the use of unsymmetrical diaryliodonium salts
in arylation reactions requires control of the chemoselectivi-
ty to avoid transfer of the wrong aryl group onto the nucleo-
phile. The factors that influence the observed chemoselectiv-
ities in metal-free reactions are poorly understood and a
thorough chemoselectivity investigation with a systematic
variation of both electronic and steric properties of the dia-
ryliodonium salts has been lacking.
Hypervalent iodine compounds have emerged as selective
and environmentally benign reagents in many areas of or-
ganic synthesis.[1] Diaryliodonium salts (Ar2IX), also named
diaryl-l3-iodanes, serve as versatile electrophilic arylating
agents with a variety of carbon and heteroatom nucleophiles
under both metal-free and metal-catalyzed conditions.[2]
Unsymmetrical diaryliodonium salts (Ar1 ¼Ar2) are re-
quired in enantioselective arylation reactions with chiral
salts,[3] as well as in the search for catalytic arylation condi-
tions or polymer-bound salts.[4] Furthermore, the synthesis of
an unsymmetrical salt is often more facile than the corre-
sponding symmetrical salt, because salts with one electron-
poor and one electron-rich moiety are readily prepared,
whereas very electron-rich or electron-poor symmetrical
salts are more difficult to obtain.[2a,5] Likewise, the synthesis
of sterically hindered, symmetrical salts is cumbersome. An-
other advantage of unsymmetrical salts is seen if an expen-
sive or non-commercial aryl group is to be transferred, be-
cause the waste of an expensive aryl-iodide moiety can be
avoided.
It is generally accepted that diaryliodonium salts react
with nucleophiles under metal-free conditions to form a T-
ꢀ
shaped Ar2I Nu intermediate, with the nucleophile and one
of the aryl groups in the hypervalent three-center-four-elec-
tron (3c-4e) bond (Scheme 1). The reaction proceeds by
Scheme 1. Chemoselectivity in metal-free arylation reactions with diaryl-
iodonium salts.
[a] J. Malmgren, Dr. S. Santoro, Dr. N. Jalalian, Prof. F. Himo,
Prof. B. Olofsson
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University, 106 91 Stockholm (Sweden)
Fax : (+46)8-154908
ligand coupling (reductive elimination) between the nucleo-
phile and the equatorial aryl group.[6] Thus, reactions with
unsymmetrical salts will give two T-shaped intermediates,
which are in fast equilibrium through Berry pseudorota-
tion.[6e] A direct nucleophilic aromatic substitution (SNAr) at
the ipso-carbon atom has also been suggested[7] and a single
electron transfer (SET) mechanism is likely under certain
conditions.[8]
E-mail: himo@organ.su.se
berit@organ.su.se
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300860.
ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original
work is properly cited, the use is non-commercial and no modifica-
tions or adaptations are made.
Chemoselectivities that are due to electronic differences
have been explained by a polarized ligand-coupling transi-
tion state, in which the developing charges are better stabi-
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Chem. Eur. J. 2013, 19, 10334 – 10342

FULL PAPER
lized by the substituents when the more electron-deficient
group is transferred.[6d,e] A recent computational study
found a correlation between the chemoselectivity and the
natural charge differences on the ipso-carbon atom of the
aryl ligand in the hypervalent bond.[6h] On the other hand,
the ortho effect has been rationalized by the bulkiest aryl
group occupying the equatorial position in the T-shaped in-
termediate, because this position is less crowded than the
apical position.[6a] Alternatively, a rate acceleration by the
release of steric strain has been suggested, although assum-
ing a different mechanism.[6g]
Fluoride arylation with unsymmetrical salts has been well-
studied and gives good chemoselectivities based on electron-
ic factors.[16] Few of the salts that are used in F-arylation
have ortho substituents,[7d,17] but Pike and Widdowson have
shown that ortho effects are indeed present.[18] DiMagno
and co-workers recently designed cyclophane-derived diary-
liodonium salts that gave good chemoselectivities with a
range of nucleophiles.[19] However, these salts were synthe-
sized in moderate yields over several steps and are therefore
unattractive for application in standard arylation reactions.
Opposite trends in chemoselectivity are observed with di-
aryliodonium salts in the presence of a transition-metal cata-
lyst. In this case, the more electron-rich or least bulky aryl
group is generally transferred and the selectivity is easier to
predict and control.[2]
The a-arylation of b-dicarbonyl compounds with diarylio-
donium salts has been well-investigated,[6d,9] including a the-
oretical study that showed two different T-shaped iodine-
ACHTUNGTRENNUNG
(III) intermediates with a low isomerization barrier.[10] Prod-
ꢀ
uct formation through [2,3] rearrangement from the O I in-
We have designed twelve unsymmetrical diaryliodonium
salts to study how variations in the steric bulk and electronic
properties influence the arylation of nucleophiles under
metal-free conditions (Figure 1).[20] These salts contain one
termediate was favored over [1,2] rearrangement from the
[10]
ꢀ
C I intermediate. Previous calculations on fluoride aryla-
tion with unsymmetrical heteroaryl salts have shown that
chemoselectivity predictions must be based on relative tran-
sition-state (TS) energies rather than the stability of the T-
shaped intermediates.[11]
Herein, we have performed a systematic study with three
different types of nucleophiles to clarify the factors that in-
fluence the chemoselectivity and to find a suitable “dummy
group” in metal-free arylation reactions with unsymmetrical
iodonium salts. Further experiments have been performed
to understand the reaction mechanism and to investigate an
observed ligand exchange in the salts. Density functional
theory (DFT) calculations have been carried out to shed
more light on the origin of the observed selectivities. The re-
sults described herein will aid further mechanistic investiga-
tions and simplify the design of diaryliodonium salts that are
suitable for asymmetric or catalytic processes.
Figure 1. Unsymmetrical diaryliodonium triflates 1 and 2 that were used
in the study.
phenyl group and one aryl group with one, two, or three
methyl (1a–1 f) or methoxy substituents (2a–2 f). The
phenyl group is always the most electron deficient and
should preferentially be transferred in the absence of other
effects (salts 1a and 2a). Salts 1b–2 f and 2b–2 f have ortho
substituents that could influence the chemoselectivity to-
wards the transfer of the aryl group instead of the phenyl
group, according to the ortho effect.
Results and Discussion
Chemoselectivity studies: In metal-free reactions, the most
electron-deficient aryl group is generally transferred, as ex-
emplified by the selective a-arylation of carbonyl com-
pounds with 2-nitrophenyl
ACHTUNGTRENNUNG
ious p-alkyl or p-methoxyphenylAHCNUTGTRENNUNG
tivity can be overruled by steric bulk in the ortho position,
thus leading to the selective transfer of that aryl group, irre-
spective of electronic properties (the so-called ortho effec-
t).[6a–c] However, there are several examples of ortho-substi-
tuted aryl groups with various electronic properties that
have not been transferred,[3,6d,e] thus making predictions and
the design of unsymmetrical salts difficult.
Phenols and carboxylic acids are arylated with good che-
moselectivity, which is either controlled by electronic factors
or ortho substituents.[13] The observed chemoselectivity with
a certain salt can otherwise vary greatly with the type of nu-
cleophile,[2a,8d,14] as demonstrated in the arylation of aniline
and fluoride with three different unsymmetrical salts.[15]
Phenol 3, aniline 6, and malonate 9 were selected to study
the phenylation versus arylation of O, N, and C nucleophiles
under previously reported conditions (Scheme 2).[9,13b,15] The
combined yields of the isolated phenylated and arylated
products are given in Scheme 2; they were consistently high
in the synthesis of diaryl ethers, but varied considerably
with the salt for the other nucleophiles. 3-Methoxy substitu-
ents were used on the phenol and aniline substrates to facili-
tate NMR determination of the product ratios, which are
listed in Table 1 and Table 2.
The arylation reactions of phenol 3 with methyl-substitut-
ed salts 1 closely follow the two trends described above
(Table 1): salt 1a gives a 3:1 preference for phenylation, in
line with the electronic effects, whereas salt 1b follows the
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10335

F. Himo, B. Olofsson et al.
that is, salts 1c and 1d give
lower selectivities than salt 1b,
despite them containing anoth-
er electron-donating substitu-
ent. In fact, one ortho substitu-
ent gives a 10/11 ratio of 11:1
(1b) and two ortho substituents
give complete selectivity for the
phenylation product (1e and
1 f). This trend has not previ-
ously been reported and can be
termed an “anti-ortho effect”.
Scheme 2. Arylation conditions for: a) phenols,[13b] b) anilines,[15] and c) malonates.[9]
Methoxy-substituted salts
2
were completely chemoselec-
tive for the phenylation of
Table 1. Phenylation versus arylation of 3, 6, and 9 with iodonium salts 1.[a]
phenol 3 to yield compound 4, irrespective of the
substitution pattern (Table 2). The electronic effect
apparently overrides the steric effect completely in
the reactions with compound 3. Arylation of aniline
6 proceeded with moderate selectivity with mono-
substituted salts 2a and 2b, thus matching the
trends seen with salts 1. Complete selectivity for
product 7 was observed with salts 2c, 2e, and 2 f,
whereas salt 2d only gave a 2.3:1 ratio. The differ-
ent outcomes with salts 2c and 2d are in accord-
ance with the switch of an electron-donating p-
OMe substituent for an electron-withdrawing m-
OMe substituent.[21]
The reactions between malonate 9 and monosub-
stituted salts 2a and 2b indicate the presence of an
ortho effect, which counteracts the electronic effect
that is exerted by the methoxy group, because the
selectivity is much higher with para-substituted salt
2a than with ortho-substituted salt 2b. This result is
unexpected, because the opposite effect was seen
with the methyl-substituted salts (Table 1). Disub-
stituted salts 2c–2e and trisubstituted salt 2 f all
gave complete selectivity for the phenylation reac-
tion to afford compound 10. Surprisingly, our re-
sults with 3-methoxyaniline (6) differ from those
Yield 4/5 [%]
Yield 7/8 [%]
Yield 10/11 [%]
1a
1b
1c
1d
1e
2.9:1
78
98
1.4:1
1.4:1
4.5:1
2.5:1
6.5:1
53
40
75
60
53
3.3:1
11:1
54
64
52
95
26
1:2.4
1.3:1
1:1.6
1:9
98
5.0:1
>99
98
2.0:1
only 10
1 f
1:1.9
84
15:1
50
only 10
55
[a] Combined yields of the isolated products. Product ratios are taken from 1H NMR
spectroscopy of the combined isolated products for compounds 4/5 and from crude
mixtures for compounds 7/8 and 10/11.
ortho effect and salts 1c and 1d give unselective reactions,
owing to the two factors opposing each other. The different
results with salts 1c and 1d are in accordance with the p-Me
substituent being more electron donating than a m-Me sub-
stituent.[21] Salt 1e shows a strong ortho effect, whereas the
poor selectivity with trisubstituted salt 1 f is a combination
of the results with salts 1a and 1e, as expected.
In contrast, the reactions with aniline 6 gave preferential
phenylation to afford compound 7 in all cases, thus indicat-
ing that the ortho effect is not present for this nucleophile.
One methyl substituent gives a slight selectivity (1a and
1b), which is increased with two methyl substituents (1c–
1e), and mesityl salt 1 f gives high selectivity for compound
7.
that were previously reported with aniline and salts 1 f and
2a with
a trifluoroacetate anion instead of a triflate
anion.[15,22] The results with malonate 9 matched previously
reported values in terms of the product ratios, although
lower yields were consistently observed.[9,23]
To summarize the chemoselectivity results, any methoxy-
substituted aryl moiety (as in 2) can be used as a dummy
ligand to control the chemoselectivity in the arylation reac-
tions of compound 3, whereas the di- or trimethoxy aryl
groups in salts 2c and 2 f are the most convenient dummy li-
gands for chemoselective transfer with compounds 6 and 9.
Salts that contain a 2,6-dimethoxy group (e.g., 2e) also give
complete chemoselectivity, but are more difficult to synthe-
size.
The results that were obtained with malonate 9 are more
difficult to rationalize, because salts 1 all preferentially give
the phenylation product, but the results are not additive,
In this study, the phenyl group was the most electron-defi-
cient group in all of the salts that were used. Based on pre-
vious reports, electron-withdrawing aryl groups are expected
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Arylation with Unsymmetrical Diaryliodonium Salts
FULL PAPER
Table 2. Phenylation versus arylation of 3, 6, 9 with iodonium salts 2.[a]
tions, because only one aryl group can be transfer-
red from the symmetrical salts that are formed
in situ. The theoretical phenylation yield is de-
creased if arylation takes place with cation 1g’, be-
cause the formation of iodobenzene wastes one
phenyl moiety that could otherwise be transferred.
Since product 4 was obtained in 90% yield with
complete chemoselectivity, the arylation must have
mainly taken place with salt 2d, despite the pres-
ence of other salts, thus indicating that the aryl ex-
change is reversible.
Furthermore, the reaction between salt 2d and
malonate 9 showed aryl exchange to cations 1g’
and 2g’ within 5 min reaction time at room temper-
ature. Since product 10 was obtained in 57% yield
with complete chemoselectivity, cation 2g’ must be
very unreactive compared to salt 2d and cation 1g’.
The lower theoretical yield if arylation takes place
with cation 1g’ (see above) could explain the lower
yields seen throughout this study compared to the
arylation of compound 9 with Ph2IOTf (80%).
The aryl exchange was further investigated with
malonate 9 by using 2,5-dimethyl-substituted salt
1d, and the symmetrical di(2,5-dimethylphenyl)io-
donium cation (2h’) and diphenyliodonium cation
Yield 4/5 [%]
Yield 7/8 [%]
Yield 10/11 [%]
2a
2b
2c
2d
only 4
94
93
82
90
5.4:1
3.0:1
74
62
50
30
13:1
2.6:1
36
61
53
57
only 4
only 4
only 4
only 7
2.3:1
only 10
only 10
2e
2 f
only 4
only 4
>99
only 7
only 7
70
45
only 10
only 10
38
44
85
[a] Combined yields of the isolated products. Product ratios are taken from 1H NMR
spectroscopy of the combined isolated products for compounds 4/5 and from crude
mixtures for compounds 7/8 and 10/11.
to be transferred with similar or higher chemoselectivities
than the phenyl group. Reactions with salts that contain two
different electron-donating aryl groups are predicted to give
lower chemoselectivities, but follow the trends that were ob-
served in this study.
(1g) were also detected in this reaction. The chemoselectivi-
ty was followed by NMR spectroscopy throughout the reac-
tion and only changed slightly over time (from 2.1:1 to 1.9:1
over 3 h). This result either indicates that the arylation rates
with the three salts are rather similar or that the aryl ex-
change is in fast equilibrium. A control experiment in which
compound 9 was reacted with the symmetrical salts 1h and
di(p-methoxyphenyl)iodonium triflate (2h) showed that the
aryl exchange took place rapidly to form the corresponding
unsymmetrical cation, 2i’. On the contrary, no aryl exchange
was detected in a control experiment in which compound 9
Aryl exchange: DiMagno and co-workers recently reported
an unexpected aryl exchange in F-arylation with unsymmet-
rical diaryliodonium salts, thus giving symmetrical diarylio-
donium salts in the presence of the nucleophile [Eq. (1)].[17b]
and a diACHTNUTRGNE(NUG p-tolyl)iodonium triflate (1i) were reacted in the
presence of 2,6-dimethyliodobenzene, thus demonstrating
that iodine(I) is not involved in the exchange reaction.
The reactions with compounds 3 and 9 are both per-
formed at low temperatures with deprotonated nucleophiles,
whereas the arylation of compound 6 takes place at high
temperatures without added base; in fact, the addition of a
base is detrimental to the reaction. The absence of aryl ex-
change in the reactions with aniline 6 might be explained by
Intrigued by this possibility, we investigated whether an
aryl exchange also took place in our reactions. Salt 2d was
selected as test substrate, because it had given low chemose-
lectivity with aniline 6 (2.3:1). When salt 2d was stirred in
DMF at room temperature or heated at reflux in the ab-
sence of a nucleophile, no ligand exchange was seen within
1 h, according to HRMS analysis of the reaction mixture.
Moreover, when aniline 6 was reacted with salt 2d under
the normal arylation conditions, no exchange was seen and
salt 2d remained as the only diaryliodonium species
throughout the reaction.
the aniline remaining protonated in the iodineACHTNUTRGNE(UNG III) inter-
mediate. Then, it would exchange much more easily than
the anions of compounds 3 and 9, thus making exchange of
the aryl ligands more unlikely. Alternatively, the arylation
In stark contrast, the reaction of phenol 3 with salt 2d
produced HRMS peaks that corresponded to symmetrical
diaryliodonium cations 1g’ and 2g’ within 5 min reaction
time at room temperature (Scheme 3). In principle, these
species could influence the chemoselectivity in both direc-
Scheme 3. Diaryliodonium cations that were observed in the reactions of
compounds 3 and 9 with salt 2d.
Chem. Eur. J. 2013, 19, 10334 – 10342 ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org
10337

F. Himo, B. Olofsson et al.
Table 3. Calculated and experimentally observed differences in ligand-
coupling transition-state energies [kcalmolꢀ1].
experimentally gives a low chemoselectivity, which corre-
sponds to
a
barrier difference of about 0.6 kcalmolꢀ1
Entry
Nucleophile
Salt
Exptl Ph/Ar
ratio[a]
Exptl[b]
Calcd[c]
(Table 3, entry 1). The calculated barriers for the phenyl and
tolyl transfers are 17.0 and 17.5 kcalmolꢀ1, respectively, thus
giving a difference of 0.5 kcalmolꢀ1. On the other hand, the
reaction between compound 3 and salt 1e leads to preferen-
tial transfer of the more electron-rich ortho-disubstituted
aryl group, which corresponds to a difference of 1.3 kcal
molꢀ1 (Table 3, entry 2). The calculated difference in TS en-
ergies is 0.9 kcalmolꢀ1 (Figure 2).
Aniline 6 was arylated without the addition of a base and
at a much higher temperature (1308C) than the other nucle-
ophiles. The reaction with salt 1a gave a low selectivity (Ph/
Ar 1.4:1), which corresponds to a barrier of about 0.3 kcal
molꢀ1 at that temperature (Table 3, entry 3); in this case, the
energy difference between the calculated transition states
was 0.5 kcalmolꢀ1. Similarly, the reaction of compound 6
with salt 2b favored the transfer of the least electron-rich
aryl group (Table 3, entry 4). In this case, the selectivity was
slightly higher and this result was also quite accurately re-
produced by the calculations (Figure 3).
DDG°
DDG°
1
2
3
4
5
6
3
3
6
6
1a
1e
1a
2b
1d
1e
2.9:1
1:9
1.4:1
3.0:1
2.0:1
only Ph
ꢀ0.6
+1.3
ꢀ0.5
+0.9
ꢀ0.5
ꢀ1.0
ꢀ0.4
ꢀ2.0
ꢀ0.3
ꢀ0.9
9[d]
9[d]
ꢀ0.4
<ꢀ1.8[e]
[a] Ratios taken from Tables 1 and 2. [b] Differences in reaction barriers
as converted from the observed chemoselectivities based on the Eyring
equation. The temperatures of the experiments (Scheme 2) were taken
into account during the conversion of the selectivities. [c] Difference in
the Gibbs free energies between the lowest-energy transition states that
lead to the two products. Room temperature was used for nucleophiles 3
and 9, whereas 1308C was used for nucleophile 6. [d] Diethyl methylmal-
onate was modeled as dimethyl methylmalonate. [e] A difference of
1.8 kcalmolꢀ1 corresponds to a 95:5 ratio.
mechanism could be different for compound 6 compared to
compounds 3 and 9. Therefore, a mechanistic study was per-
formed, as detailed below.
Finally, we also modeled the reactivity of malonate 9, for
which the experimental results with salts 1 were somewhat
surprising. In the reaction between compound 9 and salt 1d,
which only has one ortho-methyl group, the selectivity is
only 2:1 (Table 3, entry 5). This result is reproduced by the
calculations (calculated difference of 0.4 kcalmolꢀ1). The re-
action with salt 1e gives complete selectivity for phenyla-
Mechanistic studies: To shed more light on the origin of the
chemoselectivity, we performed DFT calculations on select-
ed substrates. The transition-state energies for ligand cou-
pling from the two T-shaped isomers were calculated and
compared and, in general, very good agreement was found
with the experimentally ob-
served selectivities (Table 3).
The calculated energy differ-
ences between the transition
states that lead to the two dif-
ferent products can only be di-
rectly compared under Curtin–
Hammett conditions, that is,
when the isomerization be-
tween the two T-shaped inter-
mediates is faster than the
ligand-coupling step. Indeed,
the calculated barrier for iso-
merization in one representa-
tive reaction (between salt 1a
and phenol 3) was much lower
than the barriers for the two
possible ligand-coupling reac-
tions (11.8 vs. 17.0 kcalmolꢀ1, as
the lowest barrier for ligand
coupling). This result is in
agreement with the results of
previous calculations.[6h,10,11]
The calculations very nicely
reproduced the observed exper-
imental selectivities in all of the
cases that were investigated.
For example, the reaction of io-
Figure 2. Free-energy profiles and optimized structures of starting T-shaped complexes and transition states in
the reaction of phenol 3 with salt 1e. Distances are in ꢁ and energies in kcalmolꢀ1. This Figure is provided in
donium salt 1a with phenol 3 color in the Supporting Information.
10338
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Arylation with Unsymmetrical Diaryliodonium Salts
FULL PAPER
phenoxide and arylACTHNUTRGNEUNG(phenyl)iodonium salts with seven differ-
ent para substituents. The calculated differences between
the energy barriers for phenyl or aryl transfer were correlat-
ed with the Hammett s value of the substituent
(Figure 4).[21] A good correlation was found, which showed
that the more electron-withdrawing the substituent, the
higher the chemoselectivity in favor of aryl transfer.
Figure 3. Optimized TS structures in the reaction of aniline 6 with salt 2b
and the reaction of malonate 9 with salt 1e. Distances are in ꢁ and ener-
gies in kcalmolꢀ1. This Figure is provided in color in the Supporting In-
formation.
Figure 4. Plot of the calculated relative energy barriers of phenyl/aryl
transfer versus the Hammett s values for the ligand coupling between
phenoxide and an aryl
aryl group.
ACHTUNGTREN(NUNG phenyl)iodonium salt with one para-substituted
tion, despite the presence of two ortho substituents (Table 3,
entry 6). The calculations give a difference of 2.0 kcalmolꢀ1
in favor of the phenylated product, in good agreement with
the experimental data (Figure 3). Note that, although the
aryl group occupies the equatorial position in the T-shaped
intermediate, the TS for the phenyl transfer is lower in
energy than the TS for the aryl transfer (for the free-energy
profile of this reaction, see the Supporting Information).
Thus, this result confirms the above-stated fact that chemo-
selectivity predictions must be based on the relative transi-
tion-state energies rather than on the relative energies of
the T-shaped intermediates.[11]
To analyze the source of this electronic effect, we plotted
the absolute barriers for ligand coupling between the phen-
oxide and the phenyl/aryl groups as a function of the Ham-
mett s value (see the Supporting Information). A good cor-
relation was found for the aryl transfer, whereas no correla-
tion was found for the phenyl transfer. This suggests that
the substituent influences the reaction barrier and, thus, the
chemoselectivity by stabilizing or destabilizing the attack of
the nucleophile on the ipso-carbon atom, rather than influ-
encing the properties of the 3c-4e bond.
The calculations reproduced the experimental chemose-
lectivities very well, thus providing further support for the
established ligand-coupling mechanism. It is also clear from
the calculations that the chemoselectivity depends on a deli-
cate balance between electronic and steric effects. In the
cases when only para substituents are present on the aryl
moiety, such as the reactions between salt 1a and nucleo-
philes 3 and 6, there are no steric effects present and, thus,
the chemoselectivity is only dictated by electronic effects.
To further assess the dependence of chemoselectivity on
electronic effects, we studied the ligand coupling between
As mentioned above, a previous theoretical study showed
that the differences in natural charge between the ipso-
carbon atom of the aryl ligands in the 3c-4e bond correlated
well with the calculated selectivity for meta- and para-substi-
tuted aryl compounds, whereas aryl ligands with ortho sub-
stituents did not follow the same pattern.[6h] It was also sug-
gested that the polarity of the 3c-4e bond correlated with ex-
perimental Hammett s parameters.[6h] These findings can be
reconciled with our results by simply recognizing that the
charge on the ipso-carbon atom indirectly reflects the induc-
tive effect of the substituent. Therefore, we believe that the
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F. Himo, B. Olofsson et al.
use of the Hammett s correlation is a more straightforward
siderably lowered the yield of the arylation reactions with
both salts 1a and 2b, without altering the chemoselectivity.
The accurate calculated reproduction of the observed se-
lectivities gives indirect support to the ligand-coupling
mechanism, although the factors that govern the reaction
outcome in the ligand-coupling mechanism studied herein
could be the same as those that dictate the selectivity in a
hypothetical radical mechanism.
measure.[24]
Discussion: The reaction between compound 3 and iodoni-
um salt 1e, which contains ortho-methyl groups, is a clear
example of the so-called ortho effect. With this nucleophile,
the steric effect that is exerted by the methyl groups over-
rides their electron-donating properties, which would favor
phenyl transfer. The ortho effect is normally explained by
assuming that the bulkiest aryl groups prefer the equatorial
position over the apical position, because, in trigonal bipyra-
midal geometries, the latter positions are more crowded.
Our calculations show that there is indeed already a prefer-
ence (1.4 kcalmolꢀ1) for the xylyl group occupying the equa-
torial position in the T-shaped intermediate. However, it
should be noted that the TSs show considerable distortion
compared to the starting geometries (Figure 2) and, thus,
other effects could play a role in dictating the selectivity.
Analysis of the structures of the two transition states
The mechanism of aryl exchange remains unknown and
will be the subject of further studies.
Conclusion
The observed chemoselectivities vary considerably with the
type of nucleophile. The reactions of phenol 3 with methyl-
substituted salts 1 are influenced by both electronic and
ortho effects, whereas only electronic factors are important
with more electron-rich methoxy salts 2. The selectivities
that were obtained with aniline 6 were rather different from
those with phenol 3, as only the electronic properties influ-
enced the outcome and phenylation was always the major
pathway. Malonate 9 showed a clear “anti-ortho effect” with
the methyl-substituted salts 1, thus resulting in opposite che-
moselectivity to phenol 3. In contrast, the reactions of com-
pound 9 with methoxy-substituted salts 2 were influenced by
both electronic and ortho effects, although the electronic ef-
fects dominated. The di- or trimethoxy aryl groups on salts
2c and 2 f are the most convenient dummy ligands, because
complete chemoselectivity was observed with all nucleo-
philes.
A fascinating aryl-exchange was observed in the reactions
with phenol 3 and malonate 9, resulting in the formation of
two symmetrical diaryliodonium cations. The high chemose-
lectivities and good yields that were obtained in these reac-
tions indicate a large difference between the reactivities of
the three diaryliodonium species under these reaction condi-
tions.
DFT calculations showed very good agreement with the
experimental selectivities and confirmed that electronic ef-
fects favored the transfer of the most electron-poor aryl
group. This effect does not depend on an influence on the
3c-4e bond, but rather on the stabilization of the nucleophil-
ic attack on the ipso-carbon atom of the equatorial aryl
group in the ligand-coupling step. The ortho effect is based
on steric factors and is more difficult to account for because
it varies with the nucleophile. The “anti-ortho effect” ob-
served in the arylation of malonate 9 depends on the steric
repulsion between the bulky ligand and the nucleophile.
ꢀ
(TS3-1e-Ar and TS3-1e-Ph, Figure 2) shows that the breaking I C
bond is significantly elongated and that this elongation is
more pronounced when the aryl group is transferred (2.44
versus 2.37 ꢁ). It could also be possible that there is a re-
lease of the steric repulsion between the ortho-methyl
groups and the iodine atom in the TS that leads to the trans-
fer of the substituted aryl group and that this can contribute
to the lower energy of this TS compared to the one that
leads to phenyl transfer.
The arylation of malonate 9 is a special case, because a
new “anti-ortho effect” is observed with the methyl-substi-
tuted salts. A comparison of TS9-1e-Ph with TS9-1e-Ar (Figure 3)
gives valuable insight into the origin of this effect. Indeed,
ꢀ
the forming C C bond is much longer in TS9-1e-Ar than in
TS9-1e-Ph (2.93 vs. 2.72 ꢁ), thus suggesting that this “anti-
ortho effect” is due to steric repulsion between the bulky
aryl group and the malonate, which results in a preferential
transfer of the phenyl group. The same effect is present, al-
though to a lesser extent, in the arylation of compound 9
with iodonium salt 1d.
Finally, we also considered the possibility of a mechanism
that involved a direct nucleophilic attack on the ipso-carbon
atom by an external nucleophile (i.e., a nucleophile that is
not a ligand on the hypervalent iodine).[7a–c] For all of the
three nucleophiles, the calculated barriers were found to be
higher for this mechanistic proposal compared to the barrier
to the direct ligand-coupling mechanism as discussed above
(data not shown).
However, these calculations cannot completely exclude
the involvement of a radical mechanism, at least under cer-
tain reaction conditions. Experimentally, the arylation reac-
tions of both phenols[13a] and malonate 9 were found to be
insensitive towards the radical scavenger diphenylethylene
(DPE) in their reactions with diaryliodonium triflates. On
the other hand, the arylation of aniline 6 was affected by
radical scavengers,[15] because the addition of DPE or
(2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) con-
Experimental Section
Arylation of phenol 3:[13b] To a suspension of tBuOK (1.1 equiv, 43 mg,
0.37 mmol) in THF (1.5 mL) was added phenol 3 (1.0 equiv, 0.34 mmol)
at 08C and the reaction was stirred at this temperature for 15 min.
Diaryliodonium salt 1 or 2 (1.2 equiv, 0.40 mmol) was added in one por-
10340
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Arylation with Unsymmetrical Diaryliodonium Salts
FULL PAPER
tion and the reaction was stirred in an oil bath that had been preheated
to 408C until salt 1 or 2 had been completely consumed (by TLC). Then,
the reaction was quenched with water at 08C, the organic phase was sep-
arated, and the water phase was extracted with Et2O (3ꢂ10 mL). The
combined organic phases were dried (Na2SO4) and concentrated in va-
cuo. The crude material was purified by flash chromatography on silica
gel to give diaryl ethers 4 and 5 as an inseparable mixture. The product
ratio was determined by 1H NMR spectroscopy of the isolated mixture.
Arylation of aniline 6:[15] Diaryliodonium salt 1 or 2 (1 equiv, 0.25 mmol)
was dissolved in dry DMF (2 mL) and m-anisidine (1 equiv, 0.028 mL,
0.25 mmol) was added under stirring at RT. The reaction mixture was
placed in an oil bath that had been preheated to 1308C and stirred for
24 h. The reaction was treated with a 1m aqueous solution of Na2CO3
(2 mL), extracted with EtOAc (3ꢂ5 mL), and washed with water (1ꢂ
10 mL) and brine (2ꢂ10 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo. The crude material was purified by
flash chromatography on silica gel to give diarylamines 7 and 8 as an in-
separable mixture. The product ratio was determined by 1H NMR spec-
troscopy from the crude mixture.
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Acknowledgements
The work was financially supported by the Swedish Research Council.
B.O. acknowledges the Lꢃngmanska Culture Foundation, the Lars Hierta
Memorial Foundation, and the Helge Ax:son Johnson Foundation. F.H.
acknowledges financial support from the Gçran Gustafsson Foundation
and the Knut and Alice Wallenberg Foundation. Computation time was
generously provided by the Swedish National Infrastructure for Comput-
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Chem. Eur. J. 2013, 19, 10334 – 10342 ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org
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F. Himo, B. Olofsson et al.
and solvents have not been reported to influence the chemoselectiv-
ity to a large extent; see refs. [6a,7d,17a,18a]. To avoid any influ-
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2a and only compound 10 (76%) with 2 f.
[24] Hammett constants have previously been linked with the arylation
rates of fluorides with diaryliodonium salts to support an SNAr
mechanism; see ref. [7d].
[22] The authors reported that compound 1 f
phenyl/mesityl selectivity of 2.5:1, whereas compound 2a
gave a phenyl/anisyl selectivity of 1.6:1; yields were not reported.
G
a
AHCTUNGTRENNUNG
Received: March 5, 2013
Published online: June 20, 2013
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